Comparison of protein digestibility of human milk and infant formula using the INFOGEST method under infant digestion conditions.

Many improvements have been made to bring infant formula (IF) closer to human milk (HM) regarding its nutritional and biological properties. Nevertheless, the protein components of HM and IF are still different, which may affect their digestibility. This study aimed to evaluate and compare the protein digestibility of HM and IF using the infant INFOGEST digestion method. Pooled HM and a commercial IF were subjected to the infant INFOGEST method, which simulates the physiological digestion conditions of infants, with multiple directions, i.e., the curd state, SDS-PAGE, molecular weight distribution, free amino acid concentration, and in vitro protein digestion rate. HM underwent proteolysis before digestion, and tended to have a higher protein digestion rate with finer curds during gastric digestion, than the IF. However, multifaceted analyses showed that the protein digestibility of HM and IF was not significantly different after gastrointestinal digestion. In conclusion, the infant INFOGEST method showed that the digestibility of HM and IF proteins differed to some extent before digestion and after gastric digestion, but not at the end of gastrointestinal digestion. The findings of this study will contribute to the refinement of IFs with better protein digestibility in infant stomach.

Histopathological investigation of the 1p/19q-codeleted gliomas resected following alkylating agent chemotherapy.

PURPOSE: Lower grade gliomas with 1p/19q codeletion are often responsive to chemotherapy, and several of these have been treated using upfront chemotherapy and subsequent resection following tumor volume decrease. This study aimed to elucidate the histological changes and the mechanism of recurrence after alkylating agent chemotherapy in 1p/19-codeleted gliomas. METHODS: Fourteen 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agent chemotherapy were included and compared with their pre-chemotherapy specimens. Histological changes were investigated using hematoxylin-eosin staining, and changes in proliferative activity, status of glioma stem cells (GSCs), and tumor-infiltrating macrophages were assessed using immunohistochemistry for Ki-67/MIB-1, CD68 as a pan-macrophage/monocyte marker, CD163 as a presumed marker of M2 polarity, and nestin and CD133 as markers of GSCs. RESULTS: The most frequent histological findings following chemotherapy included a sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 index decreased and the number of CD68 + cells increased after chemotherapy. The increasing rate of CD68 + cells in the post-/pre-chemotherapy specimens was inversely correlated with patient prognosis but not tumor response. The number of CD163 + cells, M2/M1 + M2 ratio, and the ratio of GSCs to total tumor cells increased after chemotherapy, and those in the post-chemotherapy specimens were negatively correlated with patient prognosis. There was a correlation between the M2/M1 + M2 ratio and the ratio of GSCs in both pre- and post-chemotherapy specimens. CONCLUSION: GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agent chemotherapy in 1p/19q-codeleted gliomas.

Association between programmed cell death ligand-1 expression and extracranial metastasis in intracranial solitary fibrous tumor/hemangiopericytoma.

BACKGROUND: Intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC) often shows extracranial metastasis, and treatment options are very limited. Immune-checkpoint molecules have not been studied well in SFT/HPCs, and their role in intracranial SFT/HPCs remains unclear. METHODS: We investigated the expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and tumor-infiltrating lymphocytes (TIL) in 16 patients of intracranial SFT/HPC by immunohistochemistry to determine if correlation with prognosis exists. RESULTS: Median overall survival (OS) of 16 patients was 9.2 years, and median follow-up of alive patients was 9.9 years. Recurrence was observed in 13 (81.3%) patients, and extracranial metastasis were observed in 6 (37.5%). PD-L1 expression was observed in all 16 tumors, whereas PD-1 expression was observed in 2. CD3 and CD8 expressions were observed in TILs in 12 and 13 patients respectively. Although the ratio of PD-L1 positive-tumor cells was not associated with OS, progression-free survival, or metastasis-free survival (MFS), diffuse staining of PD-L1 showed a trend toward shorter time to treatment failure (TTF: time to either extracranial metastasis or death) (p = 0.072). Similarly, the intense staining of PD-L1 was associated with shorter MFS (p = 0.0084) and TTF (p = 0.033). CD3 or CD8 expression was not associated with any of the prognostic parameters. In the combined analysis of PD-L1 and CD8, diffuse PD-L1 staining coupled with no or sparse CD8 expression was significantly associated with a shorter TTF (p = 0.005) and showed a trend toward shorter MFS (p = 0.0611). CONCLUSIONS: PD-L1 is frequently expressed in intracranial SFT/HPCs, and diffuse or intense PD-L1 expression might be associated with the early occurrence of extracranial metastases.

Fatty Acid Composition of the Erythrocyte Membranes Varies between Early-Term, Full-Term, and Late-Term Infants in Japan.

BACKGROUND: Term infants can be categorized into 3 sub-groups: early term (37w0d to 38w6d), full term (39w0d to 40w6d), and late term (41w0d and beyond). However, the fatty acid composition among the 3 groups of term infants has not been investigated. The association between fatty acid composition and gestational period of term infants in Japan is unclear. METHODS: We assessed the fatty acid composition of maternal erythrocyte membranes in the third trimester and of cord erythrocyte membranes at birth in 212 healthy term Japanese infants using data from a prospective hospital-based cohort study. RESULTS: In maternal erythrocyte membranes, docosahexaenoic acid (DHA) levels and omega-3 index were significantly higher in the late-term group than in the early-term group. In cord erythrocyte membranes, DHA levels were not significantly different between the 3 groups; late-term infants showed significantly higher DHA/arachidonic acid (ARA) and lower 20: 3n-6 and ARA levels compared to early-term infants. Gestational period positively correlated with the DHA status in maternal and cord erythrocyte membranes. CONCLUSIONS: Fatty acid composition in maternal and cord erythrocyte membranes varies between early-, full-, and late-term infants, and the greater gestational period may contribute to the relatively high n-3 polyunsaturated fatty acids status in term infants. Furthermore, maternal DHA status in the third semester directly correlates with gestational period in pregnant Japanese women.

Molecular-genetic and clinicopathological prognostic factors in patients with gliomas showing total 1p19q loss: gain of chromosome 19p and histological grade III negatively correlate with patient's prognosis.

Although 1p19q codeleted gliomas are the most favorable molecular subgroup of lower-grade gliomas, there are cases with early recurrence or short survival. The objective of this study was to elucidate molecular-genetic and clinicopathological prognostic factors in patients with gliomas showing total 1p19q loss. The study included 57 consecutive patients with codeleted gliomas who were operated at Keio University Hospital between 1990 and 2010. These patients were assessed for chromosomal copy number aberrations, promoter methylation status of the O6-methylguanine-DNA methyltransferase gene (MGMT), and demographic and clinicopathological prognostic factors in diffuse gliomas. No significant difference was observed in the overall survival (OS) of the patients with respect to age (≥40 years vs. <40 years), degree of resection, maximum tumor diameter (≥5 cm vs. <5 cm), histological subtype, and MGMT promoter methylation status. Gain of chromosome 19p and grade III histology were associated with shorter OS (P = 0.019, 0.061, respectively). Gain of 19p and histological grade III might be negative prognostic factors for the patients with gliomas showing total 1p19q loss. Further investigation is warranted to confirm these notions.

Relationship between Changes in Fatty Acid Composition of the Erythrocyte Membranes and Fatty Acid Intake during Pregnancy in Pregnant Japanese Women.

OBJECTIVE: Docosahexaenoic acid (DHA) is an important nutrient required by pregnant women and fetuses. Several studies suggest that fatty acid composition changes during pregnancy. However, the association of longitudinal changes in erythrocyte fatty acid composition and dietary fatty acid intake during pregnancy is not well understood. We assessed the relationship between fatty acid composition of the erythrocyte membranes and fatty acid intake at each trimester in pregnant Japanese women. METHODS: We conducted a prospective hospital-based cohort study. We investigated fatty acid composition of the erythrocyte membranes and intake of fatty acids during the three trimesters in 178 healthy, pregnant Japanese women. RESULTS: The eicosapentaenoic acid and arachidonic acid percentage of the erythrocyte membranes significantly decreased. The percentages of linoleic acid and α-linolenic acid significantly increased during pregnancy. The DHA percentage in the erythrocyte membranes decreased from the second to the third trimester. The DHA percentage in the erythrocyte membranes positively correlated with DHA intake in the third trimester. CONCLUSION: In pregnant Japanese women, the fatty acid composition of the erythrocyte membranes markedly changed throughout pregnancy. The DHA intake in the third trimester may be insufficient to maintain DHA percentage in the maternal erythrocyte membranes.

The Ratio of Docosahexaenoic Acid and Arachidonic Acid in Infant Formula Influences the Fatty Acid Composition of the Erythrocyte Membrane in Low-Birth-Weight Infants.

OBJECTIVE: The arachidonic acid (ARA) and docosahexaenoic acid (DHA) contents in the infant formula influence on the growth and development of low-birth-weight infants (LBWI). In Japan, many infant formulas are fortified only with DHA. We investigated the safety and efficacy of an infant formula (H2025A) fortified with DHA and ARA (DHA/ARA ratio of 2:1, the same as that in Japanese breast milk). METHODS: In this randomized double-blind trial, 35 LBWI were randomly allocated to 2 groups fed with H2025A or an infant formula fortified only with DHA (control formula) after discharge from the NICU. The duration of this study was one month, and the growth and fatty acid composition of the erythrocyte membrane were compared between the 2 groups. RESULTS: No difference was found in the body weight gain, height gain and head circumstance gain development between the 2 groups, and no adverse event occurred in both groups. The ARA content of the erythrocyte membrane after feeding for 1 month was significantly higher in the H2025A group than in the control group. On analysis adjusted with the breast-fed ratio, the ARA and DHA contents were significantly higher in the H2025A group. CONCLUSION: It was suggested that H2025A significantly increased the ARA and DHA contents of the erythrocyte membrane of LBWI compared to the contents of the control formula.

New endoscopic classification of the cardiac orifice in esophageal achalasia: Champagne glass sign.

BACKGROUND AND AIM: Endoscopy, barium esophagram and manometry are used in the diagnosis of achalasia. In the case of early achalasia, characteristic endoscopic findings are difficult to recognize. As a result, the diagnosis of achalasia is often made several years after symptom onset. Therefore, we examined the endoscopic findings of the cardiac orifice in achalasia and propose a new classification. METHODS: A total of 400 patients with spastic esophageal motility disorders who underwent peroral endoscopic myotomy (POEM) at our hospital between March 2014 and August 2015 were screened for this study. Champagne glass sign (CG) was defined as when the distal end of the lower esophageal sphincter relaxation failure (LESRF) was proximal to the squamocolumnar junction (SCJ) and the SCJ was dilated in the retroflex view. Specifically, CG-1 was defined as a distance from the SCJ to the lower end of LESRF of <1 cm, and CG-2 was defined as a distance ≥1 cm. RESULTS: CG-0 was seen in 73 patients (28.0%), whereas the CG sign was seen in 186 patients (71.3%), of whom 170 (65.1%) were CG-1 and 16 (6.1%) were CG-2. CONCLUSIONS: The CG sign is often observed in esophageal achalasia patients. CG-0 (equal to Maki-tsuki) was observed in 28.0% of achalasia patients only. Its absence with dilated SCJ cannot be used to rule out achalasia. Barium esophagram and manometry should be done if esophageal achalasia is strongly suspected.

Upfront chemotherapy and subsequent resection for molecularly defined gliomas.

Functional preservation is critical in glioma surgery, and the extent of resection influences survival outcome. Neoadjuvant chemotherapy is a promising option because of its potential to facilitate tumor shrinkage and maximum tumor resection. The object of this study was to assess the utility of the neoadjuvant strategy in a prospective series of gliomas with favorable molecular status. Twenty-six consecutive cases of diffuse gliomas of WHO grade II or III with either 1p19q codeletion or MGMT methylation were treated with upfront chemotherapy following maximal safe removal. In cases of incomplete initial surgery, second-look resection was intended after tumor volume decrease by chemotherapy. Among 22 evaluable cases, chemotherapy led to a median change in the sum of the product of perpendicular diameters of -35 %, and 14 out of the 22 cases (64 %) showed objective response. Second-look resection after tumor volume decrease was performed in 12 out of 19 cases of incomplete initial surgery (GTR/STR 9, removal of residual methionine PET uptake 3). The median progression-free survival among the 22 patients with grade II tumors was 57 months, with some cases showing durable progression-free survival after second-look resection. MIB-1 indices of the second-look resected tumors were lower than those of the initial tumors, and the methylation status of the MGMT gene was unchanged. Neoadjuvant chemotherapy based on molecular guidance often produces significant volume decrease of incompletely resected gliomas. Radical second-look resection is an optional advantage of upfront chemotherapy for chemosensitive gliomas compared with initial radiotherapy.

Supratentorial neurenteric cyst with spontaneous repetitive intracystic hemorrhage mimicking brain abscess: a case report.

Neurenteric cyst (NC) is a benign epithelial cyst (BEC) of endodermal origin that mostly occurs in the spinal subdural space or posterior cranial fossa. A 28-year-old male presented with a left frontal lobe NC associated with spontaneous repetitive intracystic hemorrhage, which was initially diagnosed and treated as a brain abscess. He presented with headache and disorientation, without underlying diseases. A cystic tumor was suspected because of a hypointense signal on diffusion-weighted magnetic resonance imaging (MRI). One day after admission, his condition deteriorated rapidly and emergency cyst aspiration was performed. A brown viscous liquid like bloody pus comprising many neutrophils and macrophages was obtained. Although culture was negative, we initially started antibiotic treatment because of cyst content characteristics and rapid clinical course compatible with brain abscess. He was discharged without neurological deficits, but occasionally complained of intense headache. Computed tomography/MRI showed repetitive intracystic hemorrhage and gradual re-enlargement of the lesion. He underwent radical cyst excision by frontal craniotomy 34 months after aspiration. The pathological diagnosis was NC. We believe this is the first report of a supratentorial NC with spontaneous repetitive intracystic hemorrhage. BECs, especially with intracystic hemorrhage, are difficult to be distinguished from brain abscesses. In cases of cystic lesions or presumed brain abscesses refractory to treatment with aspiration and/or antibiotics, BECs should be considered, and radical cyst wall removal should be considered a treatment option.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted-prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is known for their relative chemosensitivity and indolent clinical course among diffuse gliomas of adult type. Based on the data from phase 3 clinical trials, the standard of post-surgical care for those tumors is considered to be initial chemoradiotherapy regardless of histopathological grade, particularly with PCV. However, partly due to its renewed definition in late years, prognostic factors in patients with those tumors are not well established. Moreover, the survival rate declines over 15 years, with only a 37% OS rate at 20 years for grade 3 tumors, even with the current standard of care. Given that most of this disease occurs in young or middle-aged adults, further improvements in treatment and management are necessary. Here, we discuss prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy in those tumors.

The Role of Genetic Analysis in Distinguishing Multifocal and Multicentric Glioblastomas: An Illustrative Case.

Introduction: Glioblastomas can manifest as multiple, simultaneous, noncontiguous lesions. We genetically analyzed multiple glioblastomas and discuss their etiological origins in this report. Case Presentation: We present the case of a 47-year-old woman who presented with memory impairment and left partial paralysis. Radiographic imaging revealed three apparently noncontiguous lesions in the right temporal and parietal lobes extending into the corpus callosum, leading to diagnosis of multicentric glioblastomas. All three lesions were excised. Genetic analysis of the lesions revealed a TERT promoter C228T mutation, a roughly equivalent amplification of EGFR, and homozygous deletion of CDKN2A/B exclusively in the two contrast-enhanced lesions. Additionally, the contrast-enhanced lesions exhibited the same two-base pair mutations of PTEN, whereas the non-enhanced lesion showed a partially distinct 13-base pair mutation. The other genetic characteristics were consistent. Rather than each having arisen de novo, we believe that they had developed by infiltration and are therefore best classified as multifocal glioblastomas. Conclusion: Our findings underscore anew the possibility of infiltration by glioblastomas, even within regions devoid of signal alterations on T2-weighted images or fluid-attenuated inversion recovery images. Genetic analysis can play a crucial role in differentiating whether multiple glioblastomas are multifocal or multicentric.

Detection of novel PPP1R1B::STARD3 fusion transcript in acute myeloid leukemia: a case report.

BACKGROUND: Acute myeloid leukemia (AML) is the second most common type of leukemia in children. Although prognostic and diagnostic tests of AML patients have improved, there is still a great demand for new reliable clinical biomarkers for AML. Read-through fusion transcripts (RTFTs) are complex transcripts of adjacent genes whose molecular mechanisms are poorly understood. This is the first report of the presence of the PPP1R1B::STARD3 fusion transcript in an AML patient. Here, we investigated the presence of PPP1R1B::STARD3 RTFT in a case of AML using paired-end RNA sequencing (RNA-seq). CASE PRESENTATION: A Persian 12-year-old male was admitted to Dr. Sheikh Hospital of Mashhad, Iran, in September 2019 with the following symptoms, including fever, convulsions, hemorrhage, and bone pain. The patient was diagnosed with AML (non-M3-FAB subtype) based on cell morphologies and immunophenotypical features. Chromosomal analysis using the G-banding technique revealed t (9;22) (q34;q13). CONCLUSIONS: Single-cell RNA sequencing (scRNA-seq) analysis suggested that the PPP1R1B promoter may be responsible for the PPP1R1B::STARD3 expression. Alterations in the level of lipid metabolites implicate cancer development, and this fusion can play a crucial role in the cholesterol movement in cancer cells. PPP1R1B::STARD3 may be considered a candidate for targeted therapies of the cholesterol metabolic and the PI3K/AKT signaling pathways involved in cancer development and progression.

Effect of hypoxic-ischemic insults on the composition of fatty acids in the brain of neonatal rats.

BACKGROUND: Long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA; 22:6 n-3), comprise a major component of brain membrane phospholipids. The effect of neonatal hypoxic-ischemic insults on brain fatty acid composition is not completely understood. The aim of this study was to investigate alterations in brain fatty acid composition during development and in response to hypoxic-ischemic insults in neonatal rats. METHODS: Postnatal day 7 pups were randomly assigned to two experimental groups: a control group or a hypoxic-ischemic group in which hypoxia-ischemia was produced by left common carotid artery occlusion and exposure to 8% oxygen for 1.5 h. Various brain fatty acids were measured on postnatal days 8, 10 and 14. RESULTS: On postnatal day 14, the ratio of DHA to total fatty acids increased in the control group, but not in the hypoxic-ischemic group (p < 0.05). We observed no significant differences in arachidonic acid content in the brain between the two groups. CONCLUSIONS: These results suggest that hypoxic-ischemic insults interfere with accumulation of brain DHA in developing rats. DHA supplementation may be beneficial for treating neonatal hypoxic-ischemic encephalopathy.

Methylation of the HACE1 gene is frequently detected in hepatocellular carcinoma.

BACKGROUND/AIMS: Recently, it has been reported that HACE1, the E3 ubiquitin ligase, is epigenetically inactivated in human Wilms' tumors and HACE 1 expression was also down-regulated in colorectal and gastric carcinomas. METHODOLOGY: In this study, methylation status of the HACE1 gene was examined in primary carcinomas and the corresponding normal tissues derived from 27 patients with HCC using quantitative methylation-specific PCR (qMSP). RESULTS: Methylation of the HACE1 gene was detected in 18 out of the 27 (67%) HCCs, suggesting that the methylation of HACE1 was frequently observed in HCC. The clinicopathological data were then correlated with these results. In the value of serum AFP (α-fetoprotein), a significant difference was observed (p=0.0025). CONCLUSIONS: All stages of HCCs presented HACE1 methylation, indicating that the HACE1 gene has been methylated from the early stages of HCCs.

[Medical Treatments for Malignant Brain Tumor].

Treatment of brain tumors, particularly malignant gliomas, is challenging using only surgical resection and radiation therapy, and medical treatment plays an important role in the management of these malignancies. Temozolomide has been mainly used for the treatment of malignant gliomas over a decade. However, novel therapeutic options, such as molecular-targeted drugs and oncolytic virus therapeutic agents have been introduced in recent years. Classical anticancer medications, such as nitrosoureas and platinum-based drugs, continue to be administered for treatment of some types of malignant brain tumors.

Volumetric measurement of paranasal sinuses and its clinical significance in pituitary neuroendocrine tumors operated using an endoscopic endonasal approach.

Objective: Endoscopic endonasal surgery (EES) for deep intracranial lesions has gained popularity following recent developments in endoscopic technology. The operability of invasive pituitary neuroendocrine tumors (PitNETs) depends on the anatomy of the nasal cavity and paranasal sinus. This study aimed to establish a simple volume reconstruction algorithm of the nasal cavity and paranasal sinus. Additionally, this is the first study to demonstrate the relationship between the segmentation method and the clinical significance in patients with PitNET. Methods: Pre-and postoperative tumor volumes were analyzed in 106 patients with primary (new-onset) PitNETs (80 nonfunctioning and 26 functioning) who underwent EES. The efficiency and accuracy of the semiautomatic segmentation with manual adjustments (SSMA) method was compared with other established segmentation methods for volumetric analysis in the nasal cavity and paranasal sinuses. Correlations between the measured nasal cavity and paranasal sinus volumes and the extent of tumor removal were evaluated. Results: The SSMA method yielded accurate and time-saving results following the volumetric analyses of nasal cavity and paranasal sinuses with complex structures. Alternatively, the manual and semiautomatic segmentation methods proved time-consuming and inaccurate, respectively. The sphenoid sinus volume measured by SSMA was significantly correlated with the extent of tumor removal in patients with nonfunctioning Knosp grade 3 and 4 PitNET (r = 0.318; p = 0.015). Conclusion: The volume of sphenoid sinus potentially could predict the extent of resection due to better visualization of the tumor for PitNETs with CS invasion.

Fate and Efficacy of Engineered Allogeneic Stem Cells Targeting Cell Death and Proliferation Pathways in Primary and Brain Metastatic Lung Cancer.

Primary and metastatic lung cancer is a leading cause of cancer-related death and novel therapies are urgently needed. Epidermal growth factor receptor (EGFR) and death receptor (DR) 4/5 are both highly expressed in primary and metastatic non-small cell lung cancer (NSCLC); however, targeting these receptors individually has demonstrated limited therapeutic benefit in patients. In this study, we created and characterized diagnostic and therapeutic stem cells (SC), expressing EGFR-targeted nanobody (EV) fused to the extracellular domain of death DR4/5 ligand (DRL) (EVDRL) that simultaneously targets EGFR and DR4/5, in primary and metastatic NSCLC tumor models. We show that EVDRL targets both cell surface receptors, and induces caspase-mediated apoptosis in a broad spectrum of NSCLC cell lines. Utilizing real-time dual imaging and correlative immunohistochemistry, we show that allogeneic SCs home to tumors and when engineered to express EVDRL, alleviate tumor burden and significantly increase survival in primary and brain metastatic NSCLC. This study reports mechanistic insights into simultaneous targeting of EGFR- and DR4/5 in lung tumors and presents a promising approach for translation into the clinical setting.

Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas.

Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1KO) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAFV600E/PTEN-/- and BRAFV600E/wt/PTEN-/- mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell- and T cell-mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SCN1KO-releasing GM-CSF and single-chain variable fragment anti-PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.

Molecular and genetic profiles of radiographically defined de novo meningiomas.

With the exception of radiation-induced tumors, benign meningiomas that are known to have developed within a defined time period are extremely rare. We have genetically characterized two cases of radiographically defined de novo, sporadic meningiomas--a 5-cm, left parasagittal tumor in a 61-year-old male and a 2.3-cm, right falx tumor in a 53-year-old female. Neither tumor was observed during MRIs performed for unrelated complaints 49 and 28 months before surgery, respectively. Both tumors were totally resected, and histopathological examination revealed WHO grade I meningiomas. In both cases, the MIB-1 staining indices were high for grade I meningioma (5.6% for case 1 and 9.1% for case 2), and abnormal accumulation of p53 were observed by immunohistochemistry. The two tumors shared losses of chromosome arms 1p and 7p by comparative genomic hybridization. The tumor suppressor merlin, product of the NF2 gene, was not detected in either tumor. These abnormalities found in common in both of the de novo meningiomas likely to play significant roles in the pathogenesis and/or rapid development of meningiomas. Moreover, taken together with previous studies, our findings indicate that the combined loss of 1p and 7p may play a critical role in the tumorigenesis of de novo, aggressive meningiomas.